Project 2 will test the hypothesis that SPARC (Secreted Protein Acidic and Rich in Cysteine) modulates the glomerular mesangial and epithelial cell response to injury in vivo. SPARC is an extracellular, calcium- binding, anti-adhesive protein which inhibits the proliferation of several cell types in culture, inhibits cell spreading and favors cell detachment rom extracellular matrix. SPARC inhibits proliferation of some cells by binding to PDGF to prevent PDGF -receptor interaction. Project 1 will explore the molecular mechanisms of SPARC effects on glomerular mesangial cells. In preliminary studies for Project 2, we have shown a marked upregulation of SPARC and PDGF gene expression and protein production in both glomerular epithelial and mesangial cells in response to antibody-complement mediated injury in vivo. In this project we will attempt to determine the pathophysiologic effects of SPARC in experimental renal disease in vivo.
In specific aim #1 we will test the hypothesis that SPARC may be an endogenous inhibitor of mesangial cell proliferation which favors resolution rather than progression of glomerulonephritis. This effect may involve inhibition of PDGF. We will determine the kinetics of glomerular SPARC protein production and gene expression in two models of mesangial proliferative glomerular disease, the ATS model of mesangial proliferative glomerulonephritis in which PDGF-mediated mesangial cell proliferation resolves spontaneously and the remnant kidney model in which mesangial cell proliferation is followed by progressive sclerosis. We will correlate SPARC expression with glomerular cell proliferation and PDGF gene and protein expression and determine how SPARC expression relates to recovery from glomerular injury.
In specific aim #2 we will determine whether neutralization of SPARC peptide 2.1 (which contains the anti- proliferative domain) with a specific antibody results in a more prolonged course or more severe consequences of mesangial cell proliferation i rats with mesangial proliferative GN.
In specific aim #3 we will determine whether SPARC or its derived active peptide 2.1 modulate glomerular epithelial cell proliferation. We will also assess the effects of SPARC and peptides which contain the domains which inhibit cell-matrix interactions (1.1.4.2) on glomerular epithelial cell matrix attachment and shape change in vitro and in vivo. The proposed studies should provide important new information on the mechanisms which regulate progression and resolution of glomerular injury following immunologic insults.
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| Durvasula, Raghu V; Petermann, Arndt T; Hiromura, Keiju et al. (2004) Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int 65:30-9 |
| Hudkins, Kelly L; Gilbertson, Debra G; Carling, Matthew et al. (2004) Exogenous PDGF-D is a potent mesangial cell mitogen and causes a severe mesangial proliferative glomerulopathy. J Am Soc Nephrol 15:286-98 |
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